Patent GB-921507-A (GB)
Title: Indolyl lower alkyl-tertiary amines
IPC: C07D209/18
Filed: 1961-04-10
Abstract: Acid addition salts of compounds of the general formula: <FORM:0921507/IV(a)/1> in which any two of the three free valencies in the 1-, 2- and 3-positions of the indole nucleus are taken up by hydrogen atoms and the third free valence in any one of the three positions is taken up by the -CH2-Y-N=B residue (Y representing a C2-7 alkylene radical, there being 2-5 carbon atoms between the indolylmethyl group and the amino-N atom and the group N=B representing a 1-azacycloalkanyl group containing 7 to 9 ring atoms, 1-(4-phenylazocycloheptanyl), 3-(3-azobicyclo[3,2,0]-heptanyl) or 3-(1,8,8-trimethyl-3-azobicyclo[3,2,1]-octanyl) groups), include salts formed with acidic ion exchange resins especially with "Amberlite" (Registered Trade Mark) XE-66 resin.  The salts are prepared by double decomposition.ALSO:The invention comprises indoles of the general formula <FORM:0921507/IV(a)/1> and acid addition salts thereof, in which any two of the three free valencies in the 1-, 2-and 3-positions of the indole nucleus are taken up by two hydrogen atoms and the third free valence in any one of the three positions is taken up by the -CH2-Y-N=B residue, Y representing a C2-7 alkylene radical there being 2-5 carbon atoms between the indolylmethyl group and the amino-N atom and the group N=B representing a 1-azacycloalkanyl group containing 7 to 9 ring atoms, 1-(4-phenylazacycloheptanyl), 3-(3-azabicyclo[3,2,0]heptanyl) or 3-(1,8,8-trimethyl-3-azabicyclo[3,2,1]octanyl) groups and the preparation thereof by reacting compounds of the formulae: <FORM:0921507/IV(a)/2> <FORM:0921507/IV(a)/3> <FORM:0921507/IV(a)/4> in which Y1 is a C2-6 alkylene group there being 2-4 carbon atoms between the indolylmethyl group and the amino-N atom or compounds of the formulae <FORM:0921507/IV(a)/5> <FORM:0921507/IV(a)/6> <FORM:0921507/IV(a)/7> in which N=Z is a 3-(3-azabicyclo[3,2,0]heptane-2,4-dionyl) or a 3-(1,8,8-trimethyl-3-azabicyclo[3,2,1]octane-2,4-dionyl) group with an alkali metal aluminium hydride.  3-Indolyl-alkylamines of the invention wherein Y is an alkylene residue interposing 5 carbon atoms between the indolylmethyl group and the amino-N atom may also be prepared by reduction of the e -(3-indolyl)-e -ketocaproamide of the formula <FORM:0921507/IV(a)/8> with an alkali metal aluminium hydride.  1-Indolylalkylamine are also prepared by condensing indole with a haloalkylamine Hal-Y11-N=B where Y11 is an alkylene group interposing 4-6 carbon atoms between the indole residue and the amino-N atom.  2- and 3-Indolylalkylcarboxamides IIb and IIa are prepared by saponifying and decarboxylating a dialkyl 2- or 3-indolylalkylmalonate to give a 2- or 3-indolylalkanoic acid, reacting the acid with an alkyl haloformate to give a mixed anhydride of an alkyl carbonic acid and a 2- or 3-indolylalkanoic acid and reacting the anhydride with a tertiary amine HN=B.  Dialkyl 2- or 3-indolylethyl-, -propyl-, and -butylmalonates are prepared by reducing the corresponding 2- or 3-indolylacetic, -propionic or butyric acids to the 2- or 3-indolylethanols, -propanols, or -butanols converting these to the 2- or 3-indolylethyl, -propyl, or -butyl halides and reacting these with an alkyl malonate.  2- or 3-Indoleacetic acids are prepared by reacting a quaternary ammonium salt of a 2- or 3-(dialkylaminomethyl)indole with an alkali metal cyanide to give 2- or 3-cyanomethylindole and hydrolysing this with acid.  2- or 3-Indolylmethylmalonate is prepared from a 2- or 3-(dialkylaminomethyl)indole quaternary ammonium salt and a dialkyl malonate. e -(3-Indolyl)-e -ketocaproamide, IIIa, is prepared by reacting a 3-indolyl magnesium halide with a half ester of adipic acid chloride to form the alkyl-e -(3-indolyl)-e -ketoadipate hydrolysing the ester to the free acid form the mixed anhydride of the acid with an alkyl carbonic acid and reacting the anhydride with an amine HN=B.  1-Indolylpropionamides IIc, are prepared by adding an acrylonitrile to indole to form a 1-indolylpropionitrile hydrolysing this to the propionic acid forming the mixed anhydride with an alkyl carbonic acid and reacting the anhydride with an amine HN=B.  1-, 2-, and 3-Indolylalkylcarboxamides VIc, VIb, VIa are prepared by condensing an indolylalkyl primary amine with cis 1,2-cyclobutane dicarboxylic acid anhydride or d,1-camphoric acid anhydride.  1-, 2- and 3-Indolylpropylamines are formed by reduction of the nitriles. 2- and 3-Indolylbutyl-, -pentyl- and -hexylamines are prepared by reacting the corresponding 2- or 3-indolylpropyl-, butyl- or pentylhalide with an alkali metal cyanide to form the nitrile and reducing this.  3 - (3 - Indolyl)-1-alkyl-propylamine is prepared by reacting indole with an alkyl vinyl ketone to give a b -(3-indolyl)ethyl alkyl ketone converting this into the oxime and reducing this.  1-Indolylbutyl-, -pentyl- and hexylamines are formed by reacting an appropriate N-haloalkylphthalimide with indole to give N-[-(1-indolyl)butyl-, pentyl- or hexyl]phthalimides and reducing these with hydrazine.ALSO:Pharmaceutical compositions having hypotensive activity comprise a hypotensive agent such as reserpine together with a compound of the general formula <FORM:0921507/VI/1> which any two of the three free valencies in the 1-, 2- and 3-positions are taken up by hydrogen atoms and the third free valency by the group CH2-Y-N=B (in which Y is a C2-7 alkylene group there being 2-5 carbon atoms between the indolylmethyl group and the amino-N atom and the group N=B is a 1-azacycloalkanyl group containing 7-9 ring atoms, 1-(4-phenylazacycloheptanyl), 3 - (3 - azabicyclo [3,2,0]heptanyl) or 3 - (1,8,8 - trimethyl - 3-azabicyclo [3,2,1] octanyl) groups) with or without a carrier or diluent.  Other compositions having hypotensive, sedative, local anaesthetic, monoamine oxidase inhibitory and antifungal activity comprise the compounds of the above general formula or their acid addition salts (including ion exchange resin complexes) and an inert diluent or carrier.  The compositions may be formulated as tablets, capsules, solutions, suspension, emulsions, salves and creams for oral, parenteral or topical administration.